Feasibility Study of Adjuvant Chemotherapy Using Taxane Plus Carboplatin for High-Risk Patients With Uterine Cervical Non-Squamous Cell Carcinoma After Radical Hysterectomy.

OBJECTIVE: We conducted this study to evaluate the efficacy and safety of adjuvant chemotherapy using taxane plus carboplatin (CBDCA) for high-risk stage IB-IIB patients with uterine cervical non-squamous cell carcinoma after radical hysterectomy. METHODS: Thirty-seven patients were eligible. Pelvic lymph node involvement and/or parametrial invasion were defined as high-risk factors. The patients were treated with 6 cycles of paclitaxel (PTX, 175 mg/m(2)) or docetaxel (DTX, 60 mg/m(2)) followed by CBDCA (area under the curve, 6) every 3 weeks. The primary end point was 2-year progression-free survival (PFS) rate, and the secondary end point was the assessment of adverse events. RESULTS: Twenty-two patients received PTX/CBDCA (TC) chemotherapy, and the remaining 15 patients underwent DTX/CBDCA (DC) chemotherapy. The 2-year PFS rate was 62.1% (95% confidence interval, 44.6%-75.5%). Patients receiving DC chemotherapy showed a better 2-year PFS rate compared to those with TC chemotherapy, but the difference was not statistically significant (80.0% vs 50.0%, P = 0.1400). The most common grade 3/4 adverse events were hematologic toxicities, which were generally well tolerable. Nonhematologic toxicity was generally mild. CONCLUSIONS: Taxane and CBDCA combination chemotherapy, especially DC chemotherapy, may be one of the useful adjuvant treatments for high-risk stage IB-IIB patients with uterine cervical non-squamous cell carcinoma after radical hysterectomy.

Yolk sac tumor of the ovary: a retrospective multicenter study of 33 Japanese women by Tohoku Gynecologic Cancer Unit (TGCU).

Yolk sac tumor (YST) of the ovary is a rare germ cell tumor comprising about 1% of all ovarian malignancies. YST usually occurs as a rapidly growing unilateral tumor in young women. With the introduction of cisplatin, YST has been changed from a fatal tumor to a curable tumor. The standard treatment of YST consists of fertility-preserving surgery and 3 or 4 courses of adjuvant combination chemotherapy with bleomycin, etoposide, and cisplatin (BEP). However, the long-term prognosis of BEP-treated YST patients has not been well studied. We therefore conducted a retrospective multicenter study to investigate the prognostic factors of 33 YST patients, including 25 patients treated with BEP. The median age at initial treatment was 20 years (range 10-53). There were 15 patients (at stage I), one (stage II), 16 (stage III), and one (stage IV). Nominal and grouped numerical values were analyzed by the Kaplan-Meier method. All patients had unilateral tumor, with right-side predominance (23 patients; P = 0.02). Eighteen patients had pure YST, 13 had mixed germ cell tumor with YST component, and other 2 patients were not specified. Twenty-eight patients received fertility-preserving surgery. Twenty-seven patients had optimal surgery with less than 1 cm residual tumor diameter. Median number of chemotherapy courses was 5. Median follow-up period was 49 months. The cumulative 5-year survival rate was 87%. Univariate analysis revealed the following significant prognostic factors (P < 0.05): stage, tumor diameter, and residual tumor. Extensive debulking surgery to minimize residual tumor would improve the prognosis.

Identifying prognostic factors in Japanese women with pseudomyxoma peritonei: a retrospective clinico-pathological study of the Tohoku Gynecologic Cancer Unit.

Pseudomyxoma peritonei (PMP) is a rare condition of mucinous ascites associated mainly with mucinous tumors of appendix or ovary. PMP often recurs after treatment and may eventually cause death by abdominal visceral dysfunction via compression with mucinous ascites. Although radical peritonectomy and hyperthermic intra-peritoneal chemotherapy are becoming popular globally, the optimal treatment of PMP has not been established in Japan. We conducted a retrospective multicenter study to clarify the optimal treatment and the prognostic factors of PMP. A total of 23 patients with PMP were analyzed in the Tohoku Gynecologic Cancer Unit (TGCU). Clinical and follow-up data were retrieved and a central pathology review was performed. The median follow-up period was 46 months. Eleven patients underwent complete resection. There were 7 deaths out of 13 recurrences/progressions in this period. All the recurrence/progression was confined to the abdomen. Unexpectedly, neither radical peritonectomy nor hyperthermic intra-peritoneal chemotherapy had been performed, indicating that both radical peritonectomy and hyperthermic intra-peritoneal chemotherapy are not yet popular in Japan. The medians of overall survival and disease-free period were 166 months and 30 months, respectively. Univariate and multivariate analyses revealed that the only prognostic factor was macroscopic residual tumor (P=0.022). Although chemotherapy was not a prognostic factor (P=0.16), those who received intra-peritoneal chemotherapy tended to have a better prognosis than those who received systemic or no chemotherapy (P=0.064). In conclusion, the macroscopic residual tumor is an important prognostic factor in Japanese patients with PMP.

Complete remission of ovarian small cell carcinoma treated with irinotecan and cisplatin: a case report.

BACKGROUND: Small cell carcinoma of the ovary is a rare type of ovarian carcinoma with a very poor prognosis. CASE REPORT: We report here a case of a 55-year-old woman with small cell carcinoma of the left ovary. The patient underwent cytoreductive surgery with residual tumors of 6 cm at the cul-de-sac and was found to have stage IIIc disease. After six courses of irinotecan (CPT-11) and cisplatin (CDDP) combination therapy, secondary cytoreductive surgery was performed. The patient showed no evidence of residual tumors. After an additional three courses of chemotherapy, the patient is still alive and well without evidence of disease. CONCLUSION: CPT-11 and CDDP combination chemotherapy may be effective and safe for patients with small cell carcinoma of the ovary.

Activation of estrogen receptor α by estradiol and cisplatin induces platinum-resistance in ovarian cancer cells.

Activation of Estrogen receptor (ER) α (α) promotes cell growth and influences the response of cancer cell to chemotherapeutic agents. However, the mechanism by which ERα activation antagonizes cells to chemotherapy-induced cytotoxicity remains unclear. Here, we investigated the effect of cisplatin on ERα activation. In addition, we examined whether down-regulation of ERα modulate cisplatin-mediated cytotoxicity using 2 human ovarian cancer cells (Caov-3 and Ovcar-3) transduced with ERα short hairpin RNA (shRNA). The proliferation assay showed that 17ß-estradiol (E2) induced cell proliferation via activation of Akt and extracellular signal-regulated kinase (ERK) cascades, while shRNA mediated downregulation of ERα inhibited the cell proliferation. Immunoblot analysis revealed that cisplatin induced the phosphorylation of ERα at serine 118 via ERK cascade. Luciferase assay showed that cisplatin increases transcriptional activity of estrogen-responsive element (ERE). The E2-stimulated ERα activation attenuated cisplatin-induced cytotoxicity. Meanwhile, down-regulation of ERα inhibited E2-induced protective effect on cisplatin toxicity as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Moreover, Pretreatment with E2 followed by cisplatin decreased the expression of cleaved PARP, and increased the expression of anti-apoptotic protein Bcl-2. Collectively, our findings suggest that activation of ERα by E2 and cisplatin can induce platinum-resistance by increasing the expression of anti-apoptotic protein in ovarian cancer cells. Therefore, our findings provide valuable information that ERα might be a promising therapeutic target for platinum-resistant ovarian cancer.

A phase II study of irinotecan and pegylated liposomal doxorubicin in platinum-resistant recurrent ovarian cancer (Tohoku Gynecologic Cancer Unit 104 study).

PURPOSE: We report a phase II clinical study of the combination of irinotecan (CPT-11) and pegylated liposomal doxorubicin (PLD) in platinum- and taxane-resistant recurrent ovarian cancer, based on the recommended doses determined in a phase I trial. METHODS: PLD was administered intravenously at a dose of 30 mg/m2 on day 3. CPT-11 was administered intravenously at a dose of 80 mg/m2 on days 1 and 15, according to the recommendations of the phase I study. A single course of chemotherapy lasted 28 days, and patients underwent at least 2 courses until disease progression. The primary endpoint was antitumor efficacy, and the secondary endpoints were adverse events, progression-free survival (PFS), and overall survival (OS). RESULTS: The response rate was 32.3% and the disease control rate was 64.5%. Grade 3 and 4 neutropenia, anemia, and a decrease in platelet count were observed in 17 (54.9%), 3 (9.7%), and 1 patient (3.2%), respectively. In terms of grade 3 or higher non-hematologic toxicities, grade 3 nausea occurred in 1 patient (3.2%), vomiting in 3 patients (9.7%), and grade 3 diarrhea and fatigue in 1 patient (3.2%). The median PFS and OS rates were 2 months and not reached, respectively. Of the 11 patients with a treatment-free interval (TFI) of ≥3 months, the response rate was 63.3%, and the median PFS was 7 months. CONCLUSIONS: The treatment outcomes for the 31 patients enrolled in this study were unsatisfactory. However, sub-analysis suggested that patients with a TFI of ≥3 months had a good response rate and PFS. This suggests that CPT-11/PLD combination therapy may be a chemotherapy option for platinum-resistant recurrent ovarian cancer.

Redistribution of resistance and sensitivity to platinum during the observation period following treatment of epithelial ovarian cancer.

The standard postoperative chemotherapy for epithelial ovarian cancer is a combination therapy including platinum and taxanes. The aim this study was to investigate the degree of platinum sensitivity in patients with relapsed epithelial ovarian cancer according to the treatment-free interval (TFI) and the histological tumor type. The medical records of 405 patients diagnosed with stage III/IV ovarian cancer, including 107 patients who relapsed after attaining a clinical complete response with first-line treatment, were retrospectively reviewed. The degree of platinum sensitivity was assessed by comparing the progression-free survival (PFS) following the second-line treatment. In patients with serous/endometrioid adenocarcinoma who were treated with platinum following relapse, there were significant differences in the PFS between the following groups of patients: those who relapsed within 6 months and those who relapsed between 6 and 12 months; those who relapsed between 6 and 12 months and those who relapsed between 12 and 18 months; and those who relapsed between 12 and 18 months and those who relapsed after 18 months. By contrast, in patients with clear cell/mucinous adenocarcinoma who were treated with platinum following a relapse, there were no significant differences in the PFS between patients who relapsed within 6 months and those who relapsed between 6 and 12 months, while there were significant differences in the PFS between those who relapsed between 6 and 12 months and those who relapsed after 12 months. With regard to the patients who relapsed after 12 months, the PFS of those with clear cell/mucinous adenocarcinoma was significantly shorter compared with the PFS of those with serous/endometrioid adenocarcinoma. Therefore, we considered it justified to classify patients with clear cell/mucinous adenocarcinoma who relapsed within 12 months as platinum-resistant and those who relapsed after 12 months as platinum-sensitive.

Investigation of the clinicopathological features of fallopian tube malignancy.

The present study investigated the clinico-pathological features of fallopian tube malignancy (FTM) and elucidated the biological behavior of this disorder. Data were compiled concerning FTM from 68 patients from 7 institutes. The patients included 60 cases with fallopian tube carcinoma and 8 cases with fallopian tube carcinosarcoma. The clinical stage was stage III or higher in 72% of the cases. A complete response or partial response was achieved in 56 and 10 of the 68 patients with FTM, respectively, indicating a response rate of 97.1%. The median observation period for FTM was 41 months (3 to 126 months). Three of the 19 patients with stage I/II disease (16%) and 31 of the 49 patients with stage III/IV disease (63%) experienced recurrence, with a median progression-free survival of 17.5 months, and a 3-year overall survival of 77.2%. Regarding the site of recurrence, local intraperitoneal recurrence (26.2%) and solitary recurrences in lymph nodes (19.0%) and in the liver (16.7%) were relatively frequent. Secondary debulking surgery (SDS) was performed in 15 patients (44%) out of the 34 recurrent FTMs. Conversely, recurrence was associated with ascites (carcinomatous peritonitis) in 4 of the 34 recurrent patients, but all 4 patients died. The median survival period after recurrence was 28 months: 7.5 and 30 months with and without ascites, respectively (P<0.001). A univariate analysis showed that prognosis was significantly correlated only with whether SDS could be performed. These results suggest that since FTM frequently results in solitary recurrence, aggressive recurrence treatment including SDS could improve prognosis.

Torsion of a nongravid uterus with a large ovarian cyst: usefulness of contrast MR image.

Torsion of a nongravid uterus is extremely rare. Most cases of uterine torsion occur during pregnancy. Here we report a case of nongravid uterus torsion with a large adnexal mass. A 73-year-old woman presented at the emergency room with acute abdominal pain. A preoperative diagnosis of torsion of an ovarian cyst was made and laparotomy was performed. The left ovary was twisted 360 degrees in a clockwise rotation, and the uterine corpus had also undergone a 360 degrees rotation. Total abdominal hysterectomy and bilateral salpingo-oophorectomy were carried out. Although a preoperative diagnosis of uterine torsion was not possible, it is noteworthy that in the contrast-enhanced magnetic resonance images the uterine cervix was intensely enhanced, while the uterine corpus was not. This is the first report to show the magnetic resonance imaging findings of a twisted uterus.

Endometrioid adenocarcinoma with a functioning stroma.

A case of a 70-year-old woman with endometrioid adenocarcinoma of the ovary with functioning stroma is presented. The symptom was postmenopausal bleeding. The preoperative level of serum estradiol was as high as 162.4 pg/mL, and serum gonadotropin levels were suppressed. The endometrial tissue showed hyperplastic changes. The surgical specimens consisted of a multilocular cystic ovarian tumor of 95 mm in diameter and an enlarged uterus. Histologically, the tumor was composed of proliferating, atypical, columnar cancer cells resembling early secretory endometrial cells, and condensation of plumed stromal cells resembling theca lutein cells. The diagnosis of endometrial adenocarcinoma of the ovary with functioning stroma was made. After surgery, the serum levels of estradiol decreased and of follicle-stimulating hormone increased. Almost all types of ovarian tumor have been reported to be associated with endocrine abnormalities. Mucinous epithelial ovarian tumors most commonly present with estrogenic stroma, although the frequency of endometrioid adenocarcinoma with functioning stroma is very low. Here, a rare case with the patient's clinical course and histopathologic findings is reported.

Characteristic features of ovarian borderline tumors with invasive implant.

OBJECTIVE: Since ovarian borderline tumor with invasive implant behaves as carcinoma, it should be managed like carcinoma. Since its characteristic features have not been reported, its preoperative diagnosis was thought to be impossible. We evaluated the features of MRI and macroscopic appearance in two cases of ovarian borderline tumor with invasive implant. METHODS: Borderline tumor with invasive implant was evaluated in two patients by MRI and macroscopic examination. RESULTS: In these patients, MRI revealed profuse papillary projections. Although the lesion showed high signal intensity on contrast-enhanced T1-weighted images compared with that on T1-weighted ones, most of the signal intensity on T2-weighted images was high, suggesting that the lesion is an assembly of vesicles and an obvious solid part is absent. The macroscopic appearance of the tumor showed profuse papillary projections consisting of many vesicles perforating and extending far beyond the ovarian capsule, without a solid part. The histological findings indicated serous borderline tumors with invasive implant. CONCLUSION: In these two cases, we found the characteristic features of serous borderline tumor with invasive implant by MRI and macroscopic examination. Our findings may be of clinical value since the preoperative information about the possibility of invasive implant may be quite important for the management of borderline tumor with invasive implant, especially for young patients wishing to bear children.